Field of the Invention
This invention relates to the treatment of depressive disorders.
Description of the Related Art
Depression
Depression is a common mental disorder and refers to a mental state of low (depressed) mood and aversion to activity. Symptoms associated with depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, and/or worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleeping or insomnia, overeating or appetite loss, thoughts of suicide, and suicide attempts. The presence, number, severity, frequency, and duration of these symptoms may vary from individual to individual and from time to time for a given individual.
Psychiatrists classify mental disorders, such as depression, using the classifications such as those in the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, American Psychiatric Association, Washington DC, 2000). The most common types of depression are Major Depressive Disorder (MDD), classified in the DSM-IV-TR under code 296.3x (see DSM-IV-TR at pages 349-356 for a description of Major Depressive Episode and pages 369-376 for MDD) and Dysthymic Disorder (DD), classified in the DSM-IV-TR under code 300.4 (see DSM-IV-TR at pages 345-348 and 376-381). Diagnostic criteria for MDD are, in summary, the presence of at least one Major Depressive Episode (i.e. the presence of five or more symptoms nearly every day from (1) depressed mood—may be irritable mood in children or adolescents, (2) loss of interest or pleasure in everyday activities, (3) significant weight loss or gain, or decrease or increase in appetite, (4) insomnia or hypersomnia, (5) psychomotor agitation or retardation, (6) fatigue or loss of energy, (7) feelings of worthlessness or excessive or inappropriate guilt, (8) diminished ability to think or concentrate, and (9) recurrent thoughts of death, recurrent suicidal ideation, or attempt at suicide or specific plan for suicide; including at least one of (1) and (2) present during the same 2-week period, representing a change from previous functioning; the symptoms causing clinically significant distress or impairment, and not due to the effects of a substance, medical condition, or bereavement) not better accounted for by other conditions, and lack of manic, mixed, or hypomanic episodes. Diagnostic criteria for DD are, in summary, (1) a depressed mood for most of the day for the majority of days over at least 2 years—over at least 1 year in children or adolescents, and may be irritable mood; (2) the presence, while depressed, of symptoms such as sleep disturbances, fatigue, and feelings of hopelessness; (3) no continuous period of more than 2 months during the 2 years—1 year for children or adolescents—without the symptoms in (1) and (2); and no major depressive episode present in the first 2 years—1 year for children or adolescents—of the disturbance, so that the disorder is not better accounted for by MDD. As the DSM-IV-TR notes (page 374), MDD and DD are differentiated based on severity, chronicity, and persistence, and “the differential diagnosis between them is made particularly difficult by the fact that the two disorders share similar symptoms . . . ”. Other depression conditions may develop under special circumstances, and the DSM-IV-TR includes “specifiers” such as postpartum onset (pages 422-423), and seasonal pattern (pages 425-427) as potentially applicable to MDD—referring to the conditions commonly called postpartum depression and seasonal affective disorder. The DSM-IV-TR includes under Depressive Disorder Not Otherwise Specified (code 311, pages 381-382) minor depressive disorder (episodes of at least 2 weeks of depressive symptoms but with fewer than the five items required for MDD), and recurrent brief depressive disorder (depressive episodes lasting for from 2 days to 2 weeks at least once/month for 12 months and not associated with the menstrual cycle). The DSM-IV-TR also includes under Mood Disorder Due to General Medical Condition With Depressive Features or Mood Disorder Due to General Medical Condition With Major Depressive-Like Episode (code 293.83, pages 401-406) a predominantly depressed mood that is the physiological consequence of a general medical condition; and under Adjustment Disorder With Depressed Mood (code 309.0, pages 679-683) a depressed mood in response to a stressor, which may include a medical condition. Because depressed mood is frequently associated with chronic medical conditions such as cancer and chronically painful conditions, it is convenient to consider these last three conditions together when the Adjustment Disorder With Depressed Mood is associated with a medical condition as “depressive disorders associated with a medical condition”.
The Pharmacological Treatment of Depression
A number of antidepressant medications are available for use in treating depression. They are generally characterized by their effect on naturally occurring brain chemicals:    (1) selective serotonin reuptake inhibitors (SSRIs) include citalopram (CELEXA), escitalopram (LEXAPRO), fluoxetine (PROZAC), paroxetine (PAXIL), and sertraline (ZOLOFT). These are the most common initial treatment for depression because they are safer and generally cause fewer bothersome side effects than do other types of antidepressants. The most common side effects include decreased sexual desire and delayed orgasm. Other side effects, which can include digestive problems, jitteriness, restlessness, headache, and insomnia, may decrease over time;    (2) serotonin/norepinephrine reuptake inhibitors (SNRIs) include desvenlafaxine (PRISTIQ), duloxetine (CYMBALTA), and venlafaxine (EFFEXOR XR). The side effects are similar to those caused by SSRIs and they can cause increased sweating, dry mouth, fast heart rate, and constipation;    (3) norepinephrine/dopamine reuptake inhibitors (NDRIs) include bupropion (WELLBUTRIN). Bupropion is one of the few antidepressants that does not cause sexual side effects, though at high doses it may increase the risk of seizures;    (4) atypical antidepressants include mirtazapine (REMERON) and trazodone (OLEPTRO). These antidepressants are sedating and are usually taken in the evening. The newest atypical depressant, vilazodone (VIIBRYD), has a low risk of sexual side effects but its most common side effects are diarrhea, nausea, vomiting, and insomnia;    (5) tricyclic antidepressants include desipramine (NORPRAMIN), doxepin (SILENOR), imipramine (TOFRANIL), maprotiline, protryptaline (VIVACTIL), and trimipramine (SURMONTIL). These have been used for many years and are generally as effective as newer medications—they are generally SNRIs in effect but with an antihistaminic and anticholinergic side effect—but they are generally used only when SSRI/SNRI treatment is ineffective because they tend to have more numerous and more severe side effects which can include dry mouth, blurred vision, constipation, urinary retention, bradycardia, confusion, and weight gain;    (6) monoamine oxidase inhibitors (MAOIs) include phenelzine (NARDIL) and tranylcypromine (PARNATE). These are usually prescribed only as a last resort when other medications have not worked, because they can have serious side effects. They require a strict diet because of dangerous and potentially deadly interactions with tyramine-containing foods, for example certain cheeses, pickles, and wines, and some medications including decongestants, and cannot be combined with SSRIs.
All of these and similar antidepressant medications (“conventional antidepressant therapy”) are associated with side effects of varying degrees of significance; and most take several weeks, typically three or more weeks and up to eight weeks, to take full effect and for side effects to ease.
Association of Depression with Sleep Disorders
As noted above, one of the criteria that may be used to diagnose a Major Depressive Episode is insomnia or hypersomnia; and both the scientific and popular literature note a high incidence of sleep disturbances, particularly insomnia, in individuals suffering from depression. Unfortunately, one of the common side effects of the SSRIs and SNRIs, the most common pharmacological treatments for depression, is insomnia. Manber et al., “Cognitive Behavioral Therapy for Insomnia Enhances Depression Outcome in Patients with Comorbid Major Depressive Disorder and Insomnia”, Sleep, 2008, 31(4):489-495, report that insomnia symptoms hinder response to antidepressant treatment, and that continued insomnia following the acute phase of antidepressant therapy poses a significant risk for relapse. In a pilot study with 30 individuals diagnosed with MDD and insomnia, they found that treatment for the depression with escitalopram plus treatment for the insomnia with cognitive behavioral therapy nearly doubled the rate of rate of remission of the depression (61.5%) over treatment with escitalopram plus a control quasi-desensitization therapy (33.3%), while remission of insomnia was more than 6-fold higher (50.0% compared with 7.7%).
Nasal Chemosensory Receptors, the Vomeronasal Organ, and Pherines
Nasal chemosensory receptors, including the vomeronasal organ (“VNO”; also known as “Jacobson's organ”, a bilateral chemosensory organ found in most vertebrates including humans) are found in the mucosal lining of the nasal septum and the dorsal nasal recess, and have been associated with pheromone reception in most species (see generally Muller-Schwarze and Silverstein, “Chemical Signals”, Plenum Press, New York (1980); Monti-Bloch et al., “Effect of putative pheromones on the electrical activity of the human vomeronasal organ and olfactory epithelium”, J. Steroid Biochem. Mol. Biol., 1991, 39(4):573-582; Monti-Bloch et al., “The Human Vomeronasal System: A Review”, Ann. N.Y. Acad. Sci., 1998, 855:373-389). The axons of the neuroepithelia of the nasal chemosensory receptors, including the VNO, have direct input to the hypothalamus and limbic amygdala of the brain, while the distal processes (microvilli) may serve as chemosensory receptors (Stensaas et al., “Ultrastructure of the human vomeronasal organ”, J. Steroid Biochem. Mol. Biol., 1991, 39(4):553-560).
Human pheromones delivered to the nasal septal area bind to local chemosensory receptors and trigger nerve signals that reach the brain inducing physiological and behavioral changes (Grosser et al., “Behavioral and electrophysiological effects of androstadienone, a human pheromone”, Psychoneuroendocrinology, 2000, 25:289-299). Synthetic analogs of human pheromones called pherines (substances that bind to nasal chemosensory receptors, including receptors in the VNO) can induce robust physiological, pharmacological and behavioral changes when delivered airborne to these receptors via the nasal passages. This information is supported by several studies in human volunteers using functional magnetic resonance imaging and positron emission tomography, showing that pherines selectively activate the brain areas (hypothalamus, limbic system, cingulate gyrus, anterior thalamus and prefrontal cortex) where their physiological, pharmacological and behavioral effects are integrated. Studies with several pherines have shown that, because the compounds act directly on nasal chemosensory receptors which are directly connected to the brain, administration of the compounds causes an effect on physiological markers (e.g. autonomic nervous system responses and EEG) within seconds to less than a minute, and an effect on endocrine and neurotransmitter metabolite markers within about 10-15 minutes.
Monti et al., US Patent Application Publication No. 2003/0045514, “17-methyleneandrostan-3α-ol analogs as CRH inhibitors” discloses certain 17-methyleneandrostan-3α-ol analogs as inhibitors of corticotropin releasing hormone, potentially useful as antidepressants by vomeronasal administration.